The protein known as RANTES is a member of a large family of cytokines known as chemokines, and is classified as a β-chemokine. It has a sixty-eight amino acid sequence (SEQ ID NO:1). A receptor for RANTES has recently been cloned (Gao, et al., J. Exp. Med. 177:1421-7 (1993); Neote, et al., Cell 72:415-25 (1993)), which has been shown to bind chemokines in the order of potency of MIP-1α>RANTES.
Chemokines have the ability to recruit and activate a wide variety of proinflammatory cell types, and RANTES has been shown to elicit an inflammatory response in vivo. RANTES, along with the natural ligands for the CCRS chemokine receptor, MIP-1α, MIP-1β, were found to inhibit human immune deficiency virus type-1 (“HIV-1”) infection (Cocchi, et al., Science 270:1811-1815 (1995)), leading to the identification of CCR5 as the major co-receptor for primary isolates of HIV-1, HIV-2 and SIV-1 (Deng, et al., Nature 381:661-666 (1996); Doranz, et al., Cell 85:1149-1158 (1996); Choe, et al., Cell 85:1135-1148 (1996); Chen, et al., J. Virol. 71:2705-2714 (1997); and Alkhatib, et al., Science 272:1955-1958 (1996)). However, although RANTES consistently inhibits HIV-1 replication in peripheral blood mononuclear cells, it does not block infection of primary macrophage cultures, which suggests that RANTES would not influence HIV replication in non-lymphocyte cell types.
N-terminal modifications of RANTES result in antagonists that can block HIV-1 infection without signaling calcium flux (Mack, et al., J. Exp. Med. 187:1215-1224 (1998) and Proudfoot, et al., J. Biol. Chem. 271:2599-2603 (1996)). These modifications include N-terminal truncation [RANTES 9-68] (Arenzana-Seisdedos, et al., Nature 383:400 (1996)), and addition of methionine (“Met-RANTES”) or aminooxypentane (“AOP-RANTES”) at the N-terminus of RANTES (Mack, et al., supra and Simmons, et al., Science 276:276-279 (1997)). It has been reported that the Met-RANTES and AOP-RANTES derivatives are antagonists of RANTES. Further, N-terminally modified RANTES, with a higher affinity for CCR5 than native RANTES are more potent than native RANTES in blocking infection (Simmons, et al., supra).
Chemokine receptor antagonists that are potent, selective, and achieve full receptor occupancy would clearly be useful for the treatment of HIV-1 in infected individuals. Surprisingly, compounds have been discovered with this spectrum of activity. These derivatives inhibited infection of many different cell types, including macrophages and lymphocytes.
Additionally, antagonists of RANTES effectively block its inflammatory effects, and are thus usefll for the treatment of asthma, allergic rhinitis, atopic dermatitis, viral diseases, atheroma/atheroschleosis, rheumatoid arthritis and organ transplant rejection.
Certain derivatives of RANTES are disclosed in Wells, et al., International Application WO 96/17935.